权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Adjunct gene therapy for coronary artery bypass surgery

冠状动脉搭桥手术的辅助基因治疗

基本信息

批准号：
DT/F006314/1
负责人：
Stephen Hart
金额：
$ 30.59万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2008
资助国家：
英国
起止时间：
2008 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=DT%2FF006314%2F1
关键词：
Adjunct gene therapy coronary artery

项目摘要

Coronary Artery Disease Coronary artery disease (CAD) occurs when the arteries that supply blood to the heart muscle (the coronary arteries) become hardened and narrowed due to buildup of a material called plaque on their inner walls in a process known as atherosclerosis. As the plaque increases in size, the insides of the coronary arteries get narrower and less blood can flow through them, and the heart muscle is starved of the oxygen it needs. This can result in angina, chest pain or discomfort and eventually the patient may suffer a heart attack. Cells in the heart muscle begin to die if they do not receive enough oxygen-rich blood causing permanent damage to the heart muscle. CAD is the most common type of heart disease and the leading cause of death in the United States and Europe for both men and women. Treatment For CAD A range of medicines combined with lifestyle changes are used to treat CAD initially. However, if the symptoms continue to worsen, then direct intervention by angioplasty or bypass surgery may be necessary. Angioplasty involves inflating a small balloon within the artery and pulling it through to remove the blockage, opening the narrowed coronary arteries. A device called a stent may then be placed in the artery to keep it propped open after the procedure. Alternatively, in cases where two or more arteries in the heart are blocked, coronary artery bypass graft (CABG) surgery may be necessary. In this procedure arteries or veins from other areas of the body, such as the saphenous vein from the leg, are used to bypass the narrowed coronary arteries, improving blood flow to the heart, relieving chest pain, and possibly preventing a heart attack. Vein Graft Failure in CABG CABG surgery is very effective but there is a high rate of longer-term failure. Vein grafts failure is caused by the manipulation of the vein during surgery and the exposure of the vein to the high blood pressure in the heart. After surgery the vein undergoes a repair process, which leads to a thickening of the wall of the vein. Some thickening is desirable to enable the graft to survive the high blood pressure in the heart. However, sometimes this thickening is excessive and can lead to accelerated atherosclerosis and restricted blood flow through the vein graft. There is no effective therapy available for vein graft failure and the only option is to repeat the CABG, which is a more hazardous process second time. Aims and Objectives We aim to develop gene-based treatment for vein grafts, which will be applied to the vein when it is outside the body, prior to insertion into the heart. To achieve that goal we have developed an efficient synthetic gene carrier formulation, based on a combination of genes, small pieces of protein (peptides), liposomes, which are fatty spheres that help deliver materials into cells. The formulation, called Liptide , is very efficient at inserting genes into the walls of blood vessels and has already demonstrated therapeutic efficacy in rabbits. Genes were delivered into vein grafts before surgery and one month later it was shown that vein graft thickening was less than half that of untreated controls. We now aim to develop this technology further in a large animal model, the pig, which is a better indicator of likely efficacy in man. This study will also develop tests and experiments for evaluating the safety of the treatment prior to clinical trials. Applications and Benefits Each year more than a million CABG procedures are performed. Unfortunately, although surgery is very effective, there is a high rate of longer-term graft failure with 15-20% of vein grafts failing within one year and 50% at 10 years, leading to further serious complications. An effective treatment to promote the survival of vein grafts could affect the lives of millions of patients. The same technology could then be applied to the treatment of other diseases with genes, including cancers.

冠状动脉疾病冠状动脉疾病（CAD）发生时，供应血液到心肌的动脉（冠状动脉）变得硬化和狭窄，由于在称为动脉粥样硬化的过程中，在其内壁上积聚了称为斑块的材料。随着斑块尺寸的增加，冠状动脉的内部变得越来越窄，流过它们的血液越来越少，心肌缺乏所需的氧气。这可能导致心绞痛，胸痛或不适，最终患者可能会遭受心脏病发作。心肌细胞开始死亡，如果他们没有得到足够的富氧血液造成永久性损害的心肌。CAD是最常见的心脏病类型，也是美国和欧洲男性和女性的主要死亡原因。治疗CAD一系列药物结合生活方式的改变最初用于治疗CAD。然而，如果症状继续恶化，则可能需要血管成形术或旁路手术的直接干预。血管成形术包括在动脉内膨胀一个小气球，并将其拉过以清除阻塞，打开狭窄的冠状动脉。然后，一种叫做支架的装置可以被放置在动脉中，以在手术后保持动脉保持开放。或者，在心脏中的两个或更多动脉被阻塞的情况下，冠状动脉旁路移植术（CABG）手术可能是必要的。在这种手术中，来自身体其他部位的动脉或静脉，如腿部的隐静脉，用于绕过狭窄的冠状动脉，改善流向心脏的血液，缓解胸痛，并可能预防心脏病发作。冠状动脉旁路移植术中静脉移植失败冠状动脉旁路移植术手术非常有效，但长期失败率很高。静脉移植失败是由手术期间静脉的操作和静脉暴露于心脏中的高血压引起的。手术后，静脉经历修复过程，这导致静脉壁增厚。为了使移植物能够在心脏的高血压下存活，需要进行一些增厚。然而，有时这种增厚是过度的，可导致加速动脉粥样硬化和限制通过静脉移植物的血流。静脉移植失败没有有效的治疗方法，唯一的选择是重复CABG，这是一个更危险的过程第二次。目的和目标我们的目标是开发基于基因的静脉移植物治疗，这将适用于静脉时，它是在体外，插入到心脏之前。为了实现这一目标，我们开发了一种有效的合成基因载体制剂，该制剂基于基因、小块蛋白质（肽）、脂质体的组合，脂质体是帮助将材料递送到细胞中的脂肪球。这种名为Liptide的配方在将基因插入血管壁方面非常有效，并且已经在兔子身上证明了治疗效果。在手术前将基因输送到静脉移植物中，一个月后显示静脉移植物增厚不到未处理对照的一半。我们现在的目标是在一个大型动物模型中进一步开发这项技术，猪，这是一个更好的指标，可能对人类的疗效。这项研究还将开发测试和实验，以评估临床试验前的治疗安全性。应用和益处每年有超过一百万例冠状动脉旁路移植术。不幸的是，尽管手术非常有效，但长期移植失败率很高，15-20%的静脉移植物在1年内失败，10年时失败率为50%，导致进一步严重的并发症。促进静脉移植物存活的有效治疗可能会影响数百万患者的生活。同样的技术可以应用于治疗其他基因疾病，包括癌症。